User:Marenaf/GABA transporter type 1
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GABA transporter 1 (GAT1) also known as sodium- and chloride-dependent GABA transporter 1 is a protein that in humans is encoded by the SLC6A1 gene and belongs to the solute carrier 6 (SLC6) family of transporters.[1][2][3] It mediates gamma-aminobutyric acid's translocation from the extracellular to intracellular spaces within brain tissue and the central nervous system as a whole.[4][5]
Structure
GAT1 is a 599 amino acid protein that consists of 12 transmembrane domains with an intracellular N-terminus and C-terminus.[6][4]
Function
GAT1 is a gamma-aminobutyric acid (GABA) transporter, which removes GABA from the synaptic cleft by shuttling it to presynaptic neurons (where GABA can be recycled) and astrocytes (where GABA can be broken down).[7][8] GABA Transporter 1 uses energy from the dissipation of a Na+ gradient, aided by the presence of a Cl− gradient, to translocate GABA across CNS neuronal membranes. The stoichiometry for GABA Transporter 1 is 2 Na+: 1 Cl−: 1 GABA.[9] The presence of a Cl−/Cl− exchange is also proposed because the Cl− transported across the membrane does not affect the net charge.[10] GABA is also the primary inhibitory neurotransmitter in the cerebral cortex and has the highest level of expression within it.[11] The GABA affinity (Km) of the mouse isoform of GAT1 is 8 μM.[12]
In the brain of a mature mammal, glutamate is converted to GABA by the enzyme glutamate decarboxylase (GAD) along with the addition of vitamin B6. GABA is then packed and released into the post-synaptic terminals of neurons after synthesis. GABA can also be used to form succinate, which is involved in the citric acid cycle.[13][6] Vesicle uptake has been shown to prioritize newly synthesized GABA over preformed GABA, though the reasoning behind this mechanism is currently not completely understood.
The regulation of the modular functioning of GATs is highly dependent on a multitude of second messengers and synaptic proteins.[6]
Translocation cycle
Throughout the translocation cycle, GAT1 assumes three different conformations:
- Open-to-out. In this conformation, 2 extracellular Na+ ions are co-transported into the neuron along with 1 GABA and 1 Cl− that bind to the empty transporter, thus making it fully loaded. In prokaryotes, it has been found that transport does not require Cl−. In mammals, the Cl− ion is required to offset the positive charge of the Na+ in order to maintain the proper membrane potential.[6]
- Occluded-out. Once fully loaded, this conformation prevents the release of ions/substrate into the cytoplasm or the extracellular space/synapse. The Na+, Cl−, and GABA are bound to the transporter until it changes conformation.[6]
- Open-to-in. The transporter, which was previously facing the synapse, becomes inward facing and can now release the ions and GABA into the neuron's cytoplasm. Once empty, the transporter occludes its binding site and flips to become outward facing so a new translocation cycle can begin.[6]
Clinical significance
Research has shown that schizophrenia patients have GABA synthesis and expression altered, leading to the conclusion that GABA Transporter-1, which adds and removes GABA from the synaptic cleft, plays a role in the development of neurological disorders such as schizophrenia.[14][15] GABA and its precursor glutamate have opposite functions within the nervous system. Glutamate is considered an excitatory neurotransmitter, while GABA is an inhibitory neurotransmitter. Glutamate and GABA imbalances contribute to different neurological pathologies.[13]
Imbalance in the GABAergic neurotransmission is involved in the pathophysiology of various neurological diseases such as epilepsy, Alzheimer's and stroke.[16]
A study on genetic absence epilepsy rats from Strasbourg (GAERS) found that poor GABA uptake by GAT1 caused an increase in tonic current of GABAA. In the two most understood forms of absence epilepsy, synaptic GABAA receptors including GAT1 play a major role in seizure development. Blocking GAT1 in non-epileptic control (NEC) rats caused tonic current to increase to a rate similar to that of GAERS of the same age. This common cellular control site shows a possible target for future seizure treatments.[17]
Glutamate and GABA have also been found to interact within the nucleus tractus solitarius (NTS), paraventricular nucleus (PVN), and rostral ventrolateral medulla (RVLM) of the brain to modulate blood pressure.[18]
Interactions
SLC6A1 has been shown to interact with STX1A.[19][20][21]
See also
References
- ^ Huang F, Shi LJ, Heng HH, Fei J, Guo LH (September 1995). "Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25". Genomics. 29 (1): 302–4. doi:10.1006/geno.1995.1253. PMID 8530094.
- ^ "Entrez Gene: SLC6A1 solute carrier family 6 (neurotransmitter transporter, GABA), member 1".
- ^ Scimemi, Annalisa (2014). "Structure, function, and plasticity of GABA transporters". Frontiers in Cellular Neuroscience. 8. doi:10.3389/fncel.2014.00161/full. ISSN 1662-5102.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ a b Gonzalez-Burgos, Guillermo (2010). "GABA transporter GAT1: a crucial determinant of GABAB receptor activation in cortical circuits?". Advances in Pharmacology (San Diego, Calif.). 58: 175–204. doi:10.1016/S1054-3589(10)58008-6. ISSN 1557-8925. PMID 20655483.
- ^ Johannesen, Katrine M.; Gardella, Elena; Linnankivi, Tarja; Courage, Carolina; de Saint Martin, Anne; Lehesjoki, Anna-Elina; Mignot, Cyril; Afenjar, Alexandra; Lesca, Gaetan; Abi-Warde, Marie-Thérèse; Chelly, Jamel (2018-01-08). "Defining the phenotypic spectrum of SLC6A1 mutations". Epilepsia. 59 (2): 389–402. doi:10.1111/epi.13986. ISSN 0013-9580. PMC 5912688. PMID 29315614.
- ^ a b c d e f Zafar, Sadia; Jabeen, Ishrat (2018). "Structure, Function, and Modulation of γ-Aminobutyric Acid Transporter 1 (GAT1) in Neurological Disorders: A Pharmacoinformatic Prospective". Frontiers in Chemistry. 6. doi:10.3389/fchem.2018.00397/full#b81. ISSN 2296-2646.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ Hirunsatit R, George ED, Lipska BK, Elwafi HM, Sander L, Yrigollen CM, Gelernter J, Grigorenko EL, Lappalainen J, Mane S, Nairn AC, Kleinman JE, Simen AA (January 2009). "Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity". Pharmacogenetics and Genomics. 19 (1): 53–65. doi:10.1097/FPC.0b013e328318b21a. PMC 2791799. PMID 19077666.
- ^ Madsen, Karsten K.; Hansen, Gert H.; Danielsen, E. Michael; Schousboe, Arne (2015-02-01). "The Subcellular Localization of GABA Transporters and Its Implication for Seizure Management". Neurochemical Research. 40 (2): 410–419. doi:10.1007/s11064-014-1494-9. ISSN 1573-6903.
- ^ Jin XT, Galvan A, Wichmann T, Smith Y (28 July 2011). "Localization and Function of GABA Transporters GAT-1 and GAT-3 in the Basal Ganglia". Frontiers in Systems Neuroscience. 5: 63. doi:10.3389/fnsys.2011.00063. PMC 3148782. PMID 21847373.
- ^ Loo, Donald D. F.; Eskandari, Sepehr; Boorer, Kathryn J.; Sarkar, Hemanta K.; Wright, Ernest M. (2000-12-01). "Role of Cl− in Electrogenic Na+-coupled Cotransporters GAT1 and SGLT1 *". Journal of Biological Chemistry. 275 (48): 37414–37422. doi:10.1074/jbc.M007241200. ISSN 0021-9258. PMID 10973981.
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: CS1 maint: unflagged free DOI (link) - ^ Conti, Fiorenzo; Minelli, Andrea; Melone, Marcello (2004-07-01). "GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications". Brain Research Reviews. 45 (3): 196–212. doi:10.1016/j.brainresrev.2004.03.003. ISSN 0165-0173.
- ^ Zhou, Yun; Danbolt, Niels (2013). "GABA and Glutamate Transporters in Brain". Frontiers in Endocrinology. 4. doi:10.3389/fendo.2013.00165/full. ISSN 1664-2392.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ a b Allen, Mary J.; Sabir, Sarah; Sharma, Sandeep (2022), "GABA Receptor", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30252380, retrieved 2022-04-11
- ^ Volk D, Austin M, Pierri J, Sampson A, Lewis D (February 2001). "GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons". The American Journal of Psychiatry. 158 (2): 256–65. doi:10.1176/appi.ajp.158.2.256. PMID 11156808.
- ^ Hashimoto, T; Matsubara, T; Lewis, DA (2010). "[Schizophrenia and cortical GABA neurotransmission]". Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica. 112 (5): 439–52. PMID 20560363.
- ^ Kickinger, Stefanie; Hellsberg, Eva; Frølund, Bente; Schousboe, Arne; Ecker, Gerhard F.; Wellendorph, Petrine (2019-12-15). "Structural and molecular aspects of betaine-GABA transporter 1 (BGT1) and its relation to brain function". Neuropharmacology. Neurotransmitter Transporters. 161: 107644. doi:10.1016/j.neuropharm.2019.05.021. ISSN 0028-3908.
- ^ Cope, David W.; Di Giovanni, Giuseppe; Fyson, Sarah J.; Orbán, Gergely; Errington, Adam C.; Lőrincz, Magor L.; Gould, Timothy M.; Carter, David A.; Crunelli, Vincenzo (2009-11-22). "Enhanced tonic GABAA inhibition in typical absence epilepsy". Nature Medicine. 15 (12): 1392–1398. doi:10.1038/nm.2058. ISSN 1546-170X.
- ^ Dupont, Alain G.; Légat, Laura (2020-05-25). "GABA is a mediator of brain AT1 and AT2 receptor-mediated blood pressure responses". Hypertension Research: Official Journal of the Japanese Society of Hypertension. 43 (10): 995–1005. doi:10.1038/s41440-020-0470-9. ISSN 1348-4214. PMID 32451494.
- ^ Beckman ML, Bernstein EM, Quick MW (August 1998). "Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A". The Journal of Neuroscience. 18 (16): 6103–12. doi:10.1523/JNEUROSCI.18-16-06103.1998. PMC 6793212. PMID 9698305.
- ^ Quick MW (April 2002). "Substrates regulate gamma-aminobutyric acid transporters in a syntaxin 1A-dependent manner". Proceedings of the National Academy of Sciences of the United States of America. 99 (8): 5686–91. Bibcode:2002PNAS...99.5686Q. doi:10.1073/pnas.082712899. PMC 122832. PMID 11960023.
- ^ Deken SL, Beckman ML, Boos L, Quick MW (October 2000). "Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A". Nature Neuroscience. 3 (10): 998–1003. doi:10.1038/79939. PMID 11017172. S2CID 11312913.
Further reading
- Nelson H, Mandiyan S, Nelson N (August 1990). "Cloning of the human brain GABA transporter". FEBS Letters. 269 (1): 181–4. doi:10.1016/0014-5793(90)81149-I. PMID 2387399. S2CID 34636220.
- Bennett ER, Kanner BI (January 1997). "The membrane topology of GAT-1, a (Na+ + Cl-)-coupled gamma-aminobutyric acid transporter from rat brain". The Journal of Biological Chemistry. 272 (2): 1203–10. doi:10.1074/jbc.272.2.1203. PMID 8995422.
- Bismuth Y, Kavanaugh MP, Kanner BI (June 1997). "Tyrosine 140 of the gamma-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition". The Journal of Biological Chemistry. 272 (26): 16096–102. doi:10.1074/jbc.272.26.16096. PMID 9195904.
- DeFelipe J, González-Albo MC (February 1998). "Chandelier cell axons are immunoreactive for GAT-1 in the human neocortex". NeuroReport. 9 (3): 467–70. doi:10.1097/00001756-199802160-00020. PMID 9512391. S2CID 27446580.
- Conti F, Melone M, De Biasi S, Minelli A, Brecha NC, Ducati A (June 1998). "Neuronal and glial localization of GAT-1, a high-affinity gamma-aminobutyric acid plasma membrane transporter, in human cerebral cortex: with a note on its distribution in monkey cortex". The Journal of Comparative Neurology. 396 (1): 51–63. doi:10.1002/(SICI)1096-9861(19980622)396:1<51::AID-CNE5>3.0.CO;2-H. PMID 9623887.
- Beckman ML, Bernstein EM, Quick MW (August 1998). "Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A". The Journal of Neuroscience. 18 (16): 6103–12. doi:10.1523/JNEUROSCI.18-16-06103.1998. PMC 6793212. PMID 9698305.
- Augood SJ, Waldvogel HJ, Münkle MC, Faull RL, Emson PC (January 1999). "Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human subthalamic nucleus". Neuroscience. 88 (2): 521–34. doi:10.1016/S0306-4522(98)00226-7. PMID 10197772. S2CID 2514970.
- Ong WY, Yeo TT, Balcar VJ, Garey LJ (October 1998). "A light and electron microscopic study of GAT-1-positive cells in the cerebral cortex of man and monkey". Journal of Neurocytology. 27 (10): 719–30. doi:10.1023/A:1006946717065. PMID 10640187. S2CID 39552099.
- Deken SL, Beckman ML, Boos L, Quick MW (October 2000). "Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A". Nature Neuroscience. 3 (10): 998–1003. doi:10.1038/79939. PMID 11017172. S2CID 11312913.
- Whitworth TL, Quick MW (November 2001). "Substrate-induced regulation of gamma-aminobutyric acid transporter trafficking requires tyrosine phosphorylation". The Journal of Biological Chemistry. 276 (46): 42932–7. doi:10.1074/jbc.M107638200. PMID 11555659.
- Hachiya Y, Takashima S (November 2001). "Development of GABAergic neurons and their transporter in human temporal cortex". Pediatric Neurology. 25 (5): 390–6. doi:10.1016/S0887-8994(01)00348-4. PMID 11744314.
- Quick MW (April 2002). "Substrates regulate gamma-aminobutyric acid transporters in a syntaxin 1A-dependent manner". Proceedings of the National Academy of Sciences of the United States of America. 99 (8): 5686–91. Bibcode:2002PNAS...99.5686Q. doi:10.1073/pnas.082712899. PMC 122832. PMID 11960023.
- Kanner BI (February 2003). "Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes". The Journal of Biological Chemistry. 278 (6): 3705–12. doi:10.1074/jbc.M210525200. PMID 12446715.
- Zomot E, Kanner BI (October 2003). "The interaction of the gamma-aminobutyric acid transporter GAT-1 with the neurotransmitter is selectively impaired by sulfhydryl modification of a conformationally sensitive cysteine residue engineered into extracellular loop IV". The Journal of Biological Chemistry. 278 (44): 42950–8. doi:10.1074/jbc.M209307200. PMID 12925537.
- Zhou Y, Bennett ER, Kanner BI (April 2004). "The aqueous accessibility in the external half of transmembrane domain I of the GABA transporter GAT-1 Is modulated by its ligands". The Journal of Biological Chemistry. 279 (14): 13800–8. doi:10.1074/jbc.M311579200. PMID 14744863.
- Hu JH, Ma YH, Jiang J, Yang N, Duan SH, Jiang ZH, Mei ZT, Fei J, Guo LH (January 2004). "Cognitive impairment in mice over-expressing gamma-aminobutyric acid transporter 1 (GAT1)". NeuroReport. 15 (1): 9–12. doi:10.1097/00001756-200401190-00003. PMID 15106822. S2CID 6407617.
- Korkhov VM, Farhan H, Freissmuth M, Sitte HH (December 2004). "Oligomerization of the {gamma}-aminobutyric acid transporter-1 is driven by an interplay of polar and hydrophobic interactions in transmembrane helix II". The Journal of Biological Chemistry. 279 (53): 55728–36. doi:10.1074/jbc.M409449200. PMID 15496410.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.